Repeated ethanol exposure has been shown to induce morphological, biochemical, and behavioral neuroadaptations in key brain regions in the addiction circuitry, including the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Many of these changes occur in glutamatergic receptors and scaffolding proteins at the postsynaptic density. The Homer family of proteins plays a critical role in the structure and function of the PSD. These proteins physically link glutamate receptors, the actin scaffold, and, perhaps most critical to neural plasticity, internal Ca2+ stores. Recent studies have implicated Homer2 in the regulation of expression, function and localization of excitatory receptors at the postsynaptic membrane as well as cognitive function. This raises the exciting possibility that Homer2 mediates biochemical, morphological, and behavioral adaptations following repeated ethanol exposure. Preliminary evidence demonstrates that Homer2 deletion prevents ethanol-induced spine enlargement in the NAc. Thus, the overarching hypothesis is that Homer2 regulates chronic ethanol-associated neuroadaptations of glutamatergic synapses. These studies will test the hypotheses that 1) deletion of Homer2 prevents neuroadaptations in dendritic spines and synapses in the NAc core and mPFC, 2) Homer2 regulates ethanol-induced alterations in synaptic physiology in the NAc and mPFC, and 3) deletion of Homer2 prevents behavioral adaptations and cognitive deficits resulting from repeated ethanol exposure. This work not only contributes to our understanding of the maladaptive processes that are associated with alcohol addiction, but also to our general understanding of plasticity in dendritic spines and how that relates to locomotor and cognitive behaviors. Future expansion upon this research could provide novel targets for pharmacotherapeutics to treat alcohol use disorders. PUBLIC HEALTH RELEVANCE: Repeated episodes of heavy alcohol consumption followed by withdrawal lead to increased relapse vulnerability. Long-term neuroadaptations in the medial prefrontal cortex and nucleus accumbens are associated with this vulnerability. Thus, this project seeks to elucidate the role of the postsynaptic density scaffolding protein Homer2 in ethanol-associated neuroadaptations, which could lead to the development of pharmacotherapeutics to treat alcohol use disorders.